Process for preparing substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds

ABSTRACT

A process for the preparation of substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds which has advantages over conventional processes with respect to higher conversions and yields, flexibility, a shorter overall route, environmentally acceptable conditions, influence of stereoselectivity such as diastereoselectivity in a targeted manner and at least partial suppression of the formation of undesired side-products and/or undesired stereoisomers, in particular undesired diastereomers.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/160,050, filed Jun. 14, 2011, which claims priority from U.S.provisional patent application No. 61/354,832 and from European patentapplication no. EP 10 006 201.7, both filed Jun. 15, 2010 andincorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to a process for the preparation ofsubstituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds.

A class of active ingredients having excellent analgesic effectivenessand very good tolerability are substituted3-(1-amino-2-methylpentane-3-yl)phenyl compounds such as for example(3-(3-methoxyphenyl)-2-methyl-pentyl)dimethylamine which are inter aliaknown from EP 0 693 475 B1 and WO 2008/012047 A1.

These compounds are conventionally prepared via a multi-step synthesisincluding a Mannich reaction as one of the key steps as it isexemplarily depicted below for the synthesis of(3-(3-methoxyphenyl)-2-methyl-pentyl)dimethylamine:

SUMMARY OF THE INVENTION

An object of the present invention was to provide an alternative processwhich allows for the preparation of substituted3-(1-amino-2-methylpentane-3-yl)phenyl compounds. A further object ofthe present invention was to provide such a process that has advantagesover conventional processes for the preparation of substituted3-(1-amino-2-methylpentane-3-yl)phenyl compounds, in particular withrespect to higher conversions and yields, flexibility, reducing thenumber of reaction steps, i.e. to a shorter overall route,environmentally acceptable conditions, influence of stereoselectivitysuch as diastereoselectivity in a targeted manner and at least partialsuppression of the formation of undesired side-products and/or undesiredstereoisomers, in particular undesired diastereomers.

These and other objects have been achieved by the invention describedand claimed hereinafter, i.e. by:

a process for the preparation of a compound according to formula (I),optionally in the form of one of its isolated stereoisomers, inparticular an enantiomer or diastereomer, a racemate or in form of amixture of its stereoisomers, in particular enantiomers and/ordiastereomers in any mixing ratio, or a physiologically acceptable acidaddition salt thereof,

wherein

-   R¹, R² and R³ are each independently selected from the group    consisting of H and C₁₋₄-aliphatic residues,    according to alternative A comprising the steps of    -   (a-I) hydrogenating a compound according to formula (A-I-a) or        (A-I-b), wherein R¹, R² and R³ in each case have the above        defined meanings,

-   -    to a compound according to formula (A-II), wherein R¹, R² and        R³ have the above defined meanings,

-   -   (a-II) reducing a compound according to formula (A-II) to a        compound according to formula (I),    -   (a-III) optionally converting the compound according to        formula (I) into a physiologically acceptable acid addition salt        thereof;        or according to alternative B comprising the steps of    -   (b-I) converting a compound according to formula (B-I), wherein        R³ has the above defined meaning

-   -    into a compound according to formula (I), wherein R¹, R² and R³        have the above defined meanings,    -   (b-II) optionally converting the compound according to        formula (I) into a physiologically acceptable acid addition salt        thereof,        or according to alternative C comprising the steps of    -   (c-I) hydrogenation of a compound according to formula (C-I),        wherein R³ has the above defined meaning

-   -    to a compound according to formula (C-II), wherein R³ has the        above defined meaning,

-   -   (c-II) optionally converting the thus obtained compound of        formula (C-II) into a physiologically acceptable acid addition        salt thereof    -    or    -   (c-III) optionally converting the thus obtained compound of        formula (C-II) into a compound according to formula (I), and        optionally converting the thus obtained compound according to        formula (I) into a physiologically acceptable acid addition salt        thereof.

It has been surprisingly found that by the process of the invention highconversions and yields can be achieved via a short reaction route andthat the stereoselectivity, in particular diastereoselectivity can beinfluenced in a targeted manner by the choice of the reaction conditionsand substrates. In particular, it has been surprisingly found that bythe process of the invention the stereocenters may be established viasubstrate control with almost exclusive formation of the desireddiastereomer(s), thus sparing elaborate purification or resolution stepsto separate stereoisomers and costly chiral reagents, catalysts orligands. The process of the invention does not require a Mannichreaction to be performed. In case of alternative A, a particularadvantage is the presence of a carbonyl group in the intermediateproducts such as (A-I-a) and (A-II), which allows the performance of anisomerization and/or epimerization reaction by abstracting the acidichydrogen atom at the carbon atom bound to the carbonyl group, and thusallows the synthesis of specific stereoisomers, in particulardiastereomers in a targeted manner.

For the purpose of the specification, the term “C₁₋₄-aliphatic residue”refers to a saturated or unsaturated, linear or branched acyclic andunsubstituted hydrocarbon bearing 1 to 4, i.e. 1, 2, 3 or 4 carbon atomsand encompasses a C₁₋₄-alkyl group, a C₂₋₄-alkenyl group as well as aC₂₋₄-alkynyl group. A C₂₋₄-alkenyl has at least one C—C-double bond anda C₂₋₄-alkynyl has at least one C—C-triple bond. Examples of preferredC₁₋₄-aliphatic residues are methyl, ethyl, n-propyl, isopropyl, n-butyl,sec.-butyl, isobutyl, tert.-butyl, vinyl, allyl, butenyl, butadienyl,ethynyl and propargyl. A preferred “C₁₋₄-aliphatic residue” is aC₁₋₄-alkyl, more preferably a C₁₋₄-alkyl selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl,isobutyl, tert.-butyl, even more preferably selected from the groupconsisting of methyl and ethyl. A particularly preferred C₁₋₄-aliphaticresidue is a methyl group.

For the purpose of the specification, the term “physiologicallyacceptable acid addition salt” refers to an acid addition salt of acompound such as a compound according to formula (I) and at least oneinorganic or organic acid, which are—in particular when administered toa human and/or a mammal—physiologically acceptable. In principal, anysuitable physiologically acceptable acid capable of forming such anaddition salt may be used. Suitable physiologically acceptable acidaddition salts include acid addition salts of inorganic acids, such ase.g. hydrogen chloride, hydrogen bromide and sulfuric acid, and salts oforganic acids, such as methanesulfonic acid, fumaric acid, maleic acid,acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid,mandelic acid, lactic acid, citric acid, glutaminic acid,acetylsalicylic acid, nicotinic acid, aminobenzoic acid, a-lipoic acid,hippuric acid and aspartic acid. The most preferred acid addition saltis a hydrochloride.

For the purpose of the specification, the symbol

-   -   “        ”        used in formulas throughout the present application such as for        example in formula (C-I) refers to a single bond between a first        carbon atom forming a double bond with a second carbon atom and        a substituent, indicating that the substituent bound to the        first carbon atom may be either in trans- or in cis-position (or        in (E)- or (Z)-position, respectively), with respect to the        substituent(s) bound to the second carbon atom.

As used herein the term “isolated’ when used with reference to astereoisomer, diastereomer or enantiomer means substantially separatedfrom the opposite stereoisomer, diastereomer or enantiomer, but notnecessarily from other materials.

Preferably, in the compound according to formula (I) prepared by theprocess of the invention, R¹ and R² are each independently selected fromthe group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec.-butyl, isobutyl, tert.-butyl, more preferably each independentlyselected from the group consisting of H and methyl, and R³ is preferablyselected from the group consisting of H, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl, more preferablyselected from the group consisting of H and methyl, even more preferablydenotes H.

In a preferred embodiment of the present invention, the compoundaccording to formula (I) is a compound according to formula (Ib) asdepicted below, optionally in the form of a physiologically acceptableacid addition salt, wherein R¹ and R² are each independently selectedfrom the group consisting of H and C₁₋₄-aliphatic residues.

The present invention also relates to a process for the preparation ofthe stereoisomers of the compound of formula (I), such as enantiomers ordiastereomers.

In another preferred embodiment of the present invention, the compoundof formula (I) prepared by the process of the invention is a compoundaccording to formulas (I-1), (I-2), (I-3) and/or (I-4) and any mixturein any mixing ratio thereof, optionally in the form of a physiologicallyacceptable acid addition salt, wherein R¹, R² and R³ have one of theabove defined meanings. Preferably, R³ denotes H in each of formulas(I-1), (I-2), (I-3) and (I-4).

Preferred compounds prepared by the process of the invention arecompounds according to formula (I-1) or (I-2) and any mixture in anymixing ratio thereof, optionally in the form of a physiologicallyacceptable acid addition salt, more preferably a compound of formula(I-1), optionally in the form of a physiologically acceptable acidaddition salt.

In particular, the compound of formula (I) or (Ib) prepared by theprocess of the invention is a compound according to the formula (I-1a),(I-2a), (I-3a) or (I-4a) or a mixture thereof in any mixing ratio,optionally in the form of a physiologically acceptable acid additionsalt.

namely

-   (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol (I-1a),-   (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol (I-2a),-   (1R,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol (I-3a),-   (1S,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol (I-4-a),    or any mixture thereof, optionally in the form of a physiologically    acceptable acid addition salt.

Particularly preferred compounds prepared by the process of theinvention are compounds according to formulas (I-1a) and/or (I-2a) andany mixture in any mixing ratio thereof, optionally in the form of aphysiologically acceptable acid addition salt. The most preferredcompound prepared by the process of the invention is a compoundaccording to formula (I-1a), optionally in the form of a physiologicallyacceptable acid addition salt. The compound according to formula (I-1a)is also known as Tapentadol (CAS no. 175591-23-8).

Process According to Alternative A

The process of the invention according to alternative A comprises atleast the steps (a-I) and (a-II), i.e. hydrogenation of a compoundaccording to formula (A-I-a) or (A-I-b) to a compound according toformula (A-II) (step a-I), wherein R¹, R² and R³ in each case have oneof the above defined meanings, and reducing a compound according toformula (A-II) to a compound according to formula (I), wherein R¹, R²and R³ in each case have one of the above defined meanings, (step a-II)as depicted in the following Scheme A1:

In a particularly preferred embodiment of the present invention, only acompound according to formula (A-I-b) is employed in step (a-I) ofalternative A of the process of the invention.

In another particularly preferred embodiment of the present invention,only a compound according to formula (A-I-a) is employed in step (a-I)of alternative A of the process of the invention.

Step (a-I)

Preferably, the hydrogenation step (a-I) of the process of the inventionaccording to alternative A is effected via heterogeneous or homogeneouscatalysis, in each case in the presence of hydrogen. The hydrogenemployed is preferably in gaseous form or at least part of it isdissolved in a liquid phase. In particular, the hydrogenation step (a-I)of the process of the invention according to alternative A is effectedvia heterogeneous catalysis.

The term catalyst within the context of the present invention includesboth catalytically active materials themselves and inert materials thatare provided with a catalytically active material. Accordingly, thecatalytically active material can, for example, be applied to an inertcarrier or can be present in a mixture with an inert material. Therecome into consideration as inert carrier or inert material, for example,carbon and other materials known to persons skilled in the art.

If a homogeneous catalyst in hydrogenation step (a-I) according toalternative A of the process of the invention is employed, saidhomogeneous catalyst is preferably a transition metal complex ofrhodium, iridium or ruthenium, particularly preferably a transitionmetal complex of rhodium or iridium, more particularly a transitionmetal complex of rhodium with diphosphine ligands. Diphosphine ligandswhich may preferably be employed are known, for example, from thefollowing literature references: a) H. Brunner, W. Zettlmeier, Handbookof Enantioselective Catalysis. VCH Weinheim, 1993, vol. 2; b) R. Noyoriet al. in Catalytic Asymmetric Synthesis Second Edition (I. Ojima, Ed.),Wiley-VCH, Weinheim, 2000; c) E. N. Jacobsen, A. Pfaltz, H. Yamamoto(Eds.), Comprehensive Asymmetric Catalysis Vol I-III, Springer Berlin,1999, and the references cited therein.

Particularly preferably the catalyst is selected from the groupconsisting of rhodium (−)-DIPAMP[(R,R)-(+1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane], rhodium(+)-DIPAMP[(S,S)-(+)-1,2-Bis[(2-methoxyphenyl)(phenyl)phosphino]ethane], rhodiumR-Solphos[R-(+)-N,N′-Dimethyl-7,7′-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine]and rhodium S-Solphos[S-(−)-N,N′-Dimethyl-7,T-bis(diphenylphosphino)-3,3′,4,4′-tetrahydro-8,8′-bi-2H-1,4-benzoxazine].

The reaction parameters for the homogeneous hydrogenation in step (a-I),such as, for example, pressure, temperature or reaction time, can varyover a wide range. Preferably, the temperature during the homogeneoushydrogenation in step (a-I) can be in each case from 0 to 250° C.,particularly preferably from 5 to 100° C., very particularly preferablyfrom 10 to 60° C. and most preferred from 15 to 25° C. The homogeneoushydrogenation in step (a-I) can preferably be carried out at reducedpressure, at normal pressure or at elevated pressure, preferably in therange from 0.01 to 300 bar. It is particularly preferred to carry outthe reactions under pressure in a range of from 1 to 200 bar, inparticular from 10 to 100 bar.

The reaction time can vary depending on various parameters, such as, forexample, temperature, pressure, nature of the compound to be reacted orthe properties of the catalyst, and can be determined for the process inquestion by persons skilled in the art using preliminary tests.

Heterogeneous catalysis within the context of the present inventionmeans that the catalysts employed in heterogeneous catalysis are in eachcase present in the solid state of aggregation. If a heterogeneouscatalyst in hydrogenation step (a-I) according to alternative A of theprocess of the invention is employed, said heterogeneous catalystpreferably comprises one or more transition metals, which can preferablybe selected from the group consisting of Cu, Ag, Au, Zn, Cd, Hg, V, Nb,Ta, Cr, Mo, W, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd and Pt, more preferablyfrom the group consisting of Ru, Rh, Pd, Pt and Ni, and in particularfrom the group consisting of Pd, Pt and Ni. Preferably, heterogeneouscatalysts according to the present invention can comprise one or more ofthe above-mentioned transition metals in the same or different oxidationstates. It may also be preferable for the corresponding catalysts tocontain one or more of the above-mentioned transition metals in two ormore different oxidation states. The preparation of heterogeneouscatalysts doped with transition metals can be carried out byconventional processes known to persons skilled in the art.

In particular, a heterogeneous catalyst is employed in hydrogenationreaction step (a-I) in alternative A of the process of the invention.Preferred heterogeneous catalysts employed in this steps are eachindependently selected from the group consisting of Raney nickel,palladium, palladium on carbon (1-10 wt. %, preferably 5 wt. %),platinum, platinum on carbon (1-10 wt. %, preferably 5 wt. %), rutheniumon carbon (1-10 wt. %, preferably 5 wt. %) and rhodium on carbon (1-10wt. %, preferably 5 wt. %). Most preferred is palladium on carbon (1-10wt. %, preferably 5 wt. %) as the catalyst for hydrogenation in step(a-I).

The compounds according to formula (A-I-a) or (A-I-b) according to theprocess of the invention are preferably in liquid phase and to that endare preferably mixed with or dissolved in a reaction medium that isliquid under the particular reaction conditions. Examples of suitablereaction media employed in hydrogenation reactions are methanol,ethanol, isopropanol, n-butanol, n-propanol, toluene, n-heptane,n-hexane, n-pentane, acetic acid, ethyl acetate, formic acid,hydrochloric acid, hydrobromic acid, sulfuric acid and any mixturesthereof. More preferably ethanol is used as the reaction medium in step(a-I). Of course, it is also possible to use mixtures or multiphasesystems comprising two or more of the above-mentioned liquids in theprocesses according to the present invention. A reaction insupercritical CO₂ as reaction medium is also possible.

The reaction parameters for the hydrogenation reactions in step (a-I)such as, for example, pressure, temperature or reaction time, canindependently of another vary over a wide range both. Preferably, thetemperature during the heterogeneous hydrogenation in step (a-I) is ineach case from 0 to 250° C., particularly preferably from 15 to 180° C.and very particularly preferably from 15 to 30° C. The heterogeneoushydrogenation in step (a-I) can preferably be carried out at reducedpressure, at normal pressure or at elevated pressure, preferably in therange from 0.5 to 300 bar. It is particularly preferred to carry out thereactions under pressure in a range from 0.5 to 10 bar, in particularfrom 0.75 to 10 bar. The reaction time can vary in dependence on variousparameters, such as, for example, temperature, pressure, nature of thecompound to be reacted or the properties of the catalyst, and can bedetermined for the process in question by persons skilled in the artusing preliminary tests.

The continuous removal of samples in order to monitor the reaction, forexample by means of gas chromatography (GC) methods, is also possible,optionally in combination with regulation of the corresponding processparameters.

The total amount of the heterogeneous catalyst(s) used depends onvarious factors, such as, for example, the ratio of the catalyticallyactive component to any inert material present, or the nature of thesurface of the catalyst(s). The optimal amount of catalyst(s) for aparticular reaction can be determined by persons skilled in the artusing preliminary tests.

The particular compound of formula (A-II) obtained in step (a-I) can beisolated and/or purified by conventional methods known to personsskilled in the art.

Step (a-II)

Preferably, the reduction step (a-II) of the process of the inventionaccording to alternative A is performed in the presence of at least onesuitable reducing agent. Any reducing agent suitable for the reductionof an amide group to an amine group may be employed. Preferably, thesuitable reducing agent is at least one metal hydride, more preferablyat least one metal hydride selected from the group consisting of lithiumaluminium hydride (LAH), sodium borohydride, diisobutyl aluminiumhydride (DIBAL), selectrides such as L-selectride, N-selectride andK-selectride, or the suitable reducing agent at least one borane such asborane-THF or the suitable reducing agent is hydrogen in combinationwith a catalyst, preferably in combination with a heterogeneouscatalyst. Most preferred is lithium aluminium hydride.

Preferably, in step (a-II)—in addition to the reducing agent—at leastone Lewis acid is employed in combination with the reducing agent. Aparticularly preferred Lewis acid is aluminium trichloride (AlCl₃).

Preferably, in step (a-II) the reducing agent, optionally in combinationwith a Lewis acid, is dissolved or suspended in a suitable reactionmedium and then the compound according to formula (A-II), which ispreferably dissolved in a suitable solvent, is added to the solution orsuspension comprising the reducing agent and optionally the Lewis acid.

Suitable solvents for the compound according to formula (A-II) arepreferably selected from the group consisting of methanol, ethanol,isopropanol, 1,4-dioxane, tetrahydrofuran (THF) and any mixtures in anyratio thereof. A particularly preferred solvent is THF.

Suitable reaction media for dissolving or suspending the reducing agentand optionally the Lewis acid are preferably selected from the groupconsisting of methanol, ethanol, n-propanol, isopropanol, 1,4-dioxane,tetrahydrofuran (THF) and any mixtures in any ratio thereof. Aparticularly preferred reaction medium is THF.

The reaction parameters for the reduction in step (a-II) such as, forexample, pressure, temperature or reaction time, can independently ofone another vary over a wide range both. Preferably, the temperature instep (a-II) is in each case from 0 to 250° C., particularly preferablyfrom 15 to 180° C. and very particularly preferably from 15 to 80° C.The reduction in step (a-II) can preferably be carried out at reducedpressure, at normal pressure or at elevated pressure, preferably in therange from 0.5 to 300 bar, if hydrogen in combination with a catalyst isemployed as reducing agent. It is particularly preferred to carry outthe reactions under pressure in a range from 0.5 to 10 bar, inparticular from 0.75 to 5 bar, bar, if hydrogen in combination with acatalyst is employed as reducing agent. The reaction time can vary independence on various parameters, such as, for example, temperature,pressure, nature of the compound to be reacted or the properties of thecatalyst, and can be determined for the process in question by personsskilled in the art using preliminary tests.

The particular compound of formula (I) obtained in step (a-II) can beisolated and/or purified by conventional methods known to personsskilled in the art.

Preferably, when employing a compound according to formula (A-I-a) instep (a-I) of alternative A of the process of the invention, a compoundaccording to formula (PI-3) and/or (PI-4) or any mixture in any mixingratio thereof (as preferred embodiments of a compound according toformula (A-II)) as depicted below is obtained, wherein R¹, R² and R³have one of the above defined meanings. Consequently subjecting thecompound according to formula (PI-3) and/or (PI-4) and any mixture inany mixing ratio thereof to reduction step (a-II) preferably yields acompound according to formulas (I-3) and/or (I-4) or any mixture in anymixing ratio thereof, wherein R¹, R² and R³ have one of the abovedefined meanings.

Preferably, when employing a compound according to formula (A-I-b) instep (a-I) of alternative A of the process of the invention, a compoundaccording to formula (PI-1) and/or (PI-2) or any mixture in any mixingratio thereof (as preferred embodiments of a compound according toformula (A-II)) as depicted below is obtained, wherein R¹, R² and R³have one of the above defined meanings. Consequently subjecting thecompound according to formula (PI-1) and/or (PI-2) or any mixture in anymixing ratio thereof, to reduction step (a-II) preferably yields acompound according to formula (I-1) and/or (I-2) or any mixture in anymixing ratio thereof, wherein R¹, R² and R³ have one of the abovedefined meanings.

In a particularly preferred embodiment of the present invention, only acompound according to formula (A-I-b) is employed in step (a-I) ofalternative A of the process of the invention yielding a compoundaccording to formulas (PI-1) and/or (PI-2) or any mixture in any mixingratio thereof, wherein R¹, R² and R³ have one of the above definedmeanings. Preferably, only the compounds according to formula (PI-1)and/or (PI-2) or any mixture in any mixing ratio thereof, are employedin subsequent reduction step (a-II) yielding a compound according toformulas (I-1) and/or (I-2) or any mixture in any mixing ratio thereof,wherein R¹, R² and R³ have one of the above defined meanings.

Step (a-III)

Optionally, the compound according to formula (I) may be converted intoa physiologically acceptable acid addition salt thereof. The conversionof a compound according to formula (I) into a corresponding acidaddition salt via reaction with a suitable acid or a suitable acidaddition salt forming agent may be effected in a manner well known tothose skilled in the art, e.g. by dissolving a compound according toformula (I) in at least one suitable solvent, preferably at least onesolvent selected from the group consisting of acetone, benzene,n-butanol, 2-butanone, tert.-butyl methylether, chloroform, cyclohexane,diethyl ether, 1,4-dioxane, diisopropyl ether, alkyl acetates, e.g.ethyl acetate, ethanol, n-hexane, n-heptane, isopropanol, methanol,methylene chloride (dichloromethane), n-pentane, petrol ether,n-propanol, tetrahydrofuran, toluene, and any mixture in any mixingratio thereof, and subsequent addition of at least one suitable acid orat least one acid addition salt forming agent. Preferably, the solventemployed for dissolving a compound according to formula (I) is a solventin which the resulting acid addition salt of a compound according toformula (I) is not soluble.

The precipitation and/or crystallization of the acid addition salt maypreferably be initiated and/or improved by cooling the correspondingreaction mixture and optionally partial evaporation of the solvent(s)under reduced pressure. The precipitate may then be filtered off,optionally washed with a suitable solvent, and if necessary furtherpurified by recrystallization.

The salt formation may preferably be effected in a suitable solventincluding diethyl ether, diisopropyl ether, dichloromethane, alkylacetates, e.g. ethyl acetate, acetone, 2-butanone or any mixturethereof. Preferably a reaction with trimethylchlorosilane(trimethylsilylchloride) as acid addition salt forming agent in asuitable solvent may be used for the preparation of the correspondinghydrochloride addition salt.

Step (a-IV)

In a preferred embodiment of the process of the invention, alternative Afurther comprises a step (a-IV), wherein a compound according to formula(A-0), wherein R¹, R² and R³ have one of the above defined meanings, issubjected to a dehydration reaction to obtain the compound according toformula (A-I-a),

In Scheme A2 step (a-IV) is depicted below.

The dehydration step (a-IV) is preferably acid-catalyzed oracid-promoted, i.e. performed in the presence of an acid in acatalytically effective or at least stoichiometric amount. Preferablythe acid is selected from the group consisting of formic acid,hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid,methanesulfonic acid or any mixture thereof. It is preferable if theacid is employed in a high concentration. Particularly preferably,hydrochloric acid and/or hydrobromic acid are employed. Preferably, theconcentration of the hydrochloric acid or the hydrobromic acid is >20%,more preferably >30%, particularly preferably >35% by weight.Alternatively, the acid can also be used in gaseous form.

The compound of general formula (A-0) used in step (a-IV) according tothe present invention is preferably in liquid phase and to that end ispreferably mixed with or dissolved in a reaction medium that is liquidunder the particular reaction conditions.

Examples of suitable reaction media include water, acetic acid, formicacid, toluene, hydrochloric acid, sulfuric acid, hydrobromic acid,methanesulfonic acid or any mixture thereof. Of course, it is alsopossible to use mixtures or multiphase systems comprising two or more ofthe above-mentioned liquids in the processes according to the presentinvention.

The reaction parameters for step (a-IV), such as, for example, pressure,temperature or reaction time, can vary over a wide range. It ispreferable if the reaction temperature in step (a-IV) is between 15 and100° C., particularly preferably between 18 and 80° C., moreparticularly preferably between 20 and 60° C. The dehydration step(a-IV) can preferably be carried out at reduced pressure, at normalpressure or at elevated pressure, preferably in the range from 0.01 to300 bar. It is particularly preferred to carry out the reactions underpressure in a range from 0.5 to 5 bar, in particular from 0.5 to 1.5bar.

The reaction time can vary depending on various parameters, such as, forexample, temperature, pressure, nature of the compound to be reacted orthe properties of the catalyst, and can be determined for the process inquestion by persons skilled in the art using preliminary tests.Preferably, the reaction time of step (a-IV) is between 2 and 25 h,particularly preferably between 3 and 22 h, more particularly preferablybetween 4 and 20 h.

The continuous removal of samples in order to monitor the reaction, forexample by means of gas chromatographic (GC) methods, is also possible,optionally in combination with regulation of the corresponding processparameters.

The particular compound of general formula (A-I-a) obtained can beisolated and/or purified by conventional methods known to personsskilled in the art.

Alternatively, the dehydration step (a-IV) can also be carried out inthe presence of at least one acidic catalyst, which can preferably beselected from the group consisting of ion-exchange resins, zeolites,heteropoly acids, phosphates, sulfates and optionally mixed metaloxides.

Preferably, the temperature for step (a-IV) when using an acidiccatalyst as describe above is in each case from 20 to 250° C.,particularly preferably from 50 to 180° C. and very particularlypreferably from 100 to 160° C. The ratio of acidic catalyst and compoundof formula (A-0) is preferably in the range from 1:200 to 1:1, inparticular from 1:4 to 1:2. After the dehydration, the catalyst can beseparated from the reaction mixture in a simple manner, preferably byfiltration. The particular compound of general formula (A-I-a) obtainedbe isolated and/or purified by conventional methods known to personsskilled in the art.

Alternatively, the dehydration step (a-IV) can also be carried out bysubjecting a compound of general formula (A-0) to an excess of thionylchloride, optionally in a reaction medium, preferably in a reactionmedium selected from the group consisting of diethylether,tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane,tert-butyl-methylether and any mixture thereof, and subsequent heatingof the thus obtained reaction mixture to 40° C. to 120° C., preferablyto 80° C. to 120° C.

Step (a-V)

In a preferred embodiment of the process of the invention, alternative Afurther comprises a step (a-V), wherein the compound according toformula (A-I-a) is subjected to an isomerization reaction, preferably inthe presence of a base, to obtain a compound according to formula(A-I-b). In Scheme A3 step (a-V) is depicted below.

Suitable bases to be employed are any bases which are able to abstractthe acidic proton of the carbon atom bound to the carbon atom of thecarbonyl group of the compound according to formula (A-I-a).

Preferably, suitable bases which may be employed in step (a-V) areselected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), sodium hydride (NaH), potassium hydride, sodium hydroxide (NaOH),potassium hydroxide (KOH), amines, preferably tertiary amines, morepreferably N(C₁₋₄-alkyl)₃, even more preferably triethylamine, sodiummethanolate, potassium tert-butylate (KOtBu) and mixtures of two of anyof the aforementioned bases in any mixing ratio. The most preferredbases are selected from the group consisting of potassium tert-butylate,potassium hydroxide and sodium hydride. In particular, potassiumtert-butylate is employed as a base.

Suitable reaction media for the conversion of a compound according toformula (A-1-a) into a compound to formula (A-I-b) are preferablyselected from the group consisting of acetone, benzene, n-butanol,2-butanone, tert.-butyl methylether, chloroform, cyclohexane, diethylether, 1,4-dioxane, diisopropyl ether, alkyl acetates, e.g. ethylacetate, ethanol, n-hexane, n-heptane, isopropanol, methanol, methylenechloride (dichloromethane), n-pentane, petrol ether, n-propanol,tetrahydrofuran, toluene, and any mixture in any mixing ratio thereof.Preferably, THF is used as reaction medium.

The reaction parameters for step (a-V), such as, for example, pressure,temperature or reaction time, can vary over a wide range. It ispreferable if the reaction temperature in step (a-V) is between 15 and100° C., particularly preferably between 18 and 80° C. Preferably, step(a-V) is carried out at reduced pressure, at normal pressure or atelevated pressure, preferably in the range from 0.01 to 300 bar. It isparticularly preferred to carry out the reactions under pressure in arange from 0.5 to 5 bar, in particular from 0.5 to 1.5 bar.

The reaction time can vary depending on various parameters, such as, forexample, temperature, pressure, nature of the compound to be reacted andcan be determined for the process in question by persons skilled in theart using preliminary tests. It is preferable if the reaction time ofstep (a-V) is between 2 and 25 h, particularly preferably between 3 and22 h, more particularly preferably between 4 and 20 h.

The particular compound of general formula (A-I-b) obtained can beisolated and/or purified by conventional methods known to personsskilled in the art.

Step (a-VI)

In a particularly preferred embodiment of the process of the invention,alternative A further comprises a deprotection step (a-VI), wherein oneof the compounds according to formula (A-0), (A-I-a), (A-I-b), (A-II) or(I), wherein R¹ and R² have in each case one of the above definedmeanings and R³ in each case is ≠H, is deprotected to obtain a compoundaccording to formula (Ib). Preferably, the deprotection step (a-VI) iscarried out by subjecting a compound according to formula (I) or (A-II),more preferably a compound according to formula (A-II), to saiddeprotection.

Preferably, at least one acid, preferably at least one acid selectedfrom the group consisting of hydrobromic acid, hydrochloric acid andmethanesulfonic acid is employed as deprotecting agent in step (a-VI).In case methanesulfonic acid is employed as acid a combination ofmethanesulfonic acid and methionine is preferably used as deprotectingagent. A combination of methanesulfonic acid and methionine is the mostpreferred deprotecting agent in step (a-VI). The deprotection step(a-VI) is preferably carried out in a reaction medium selected from thegroup consisting of diethylether, tetrahydrofuran, toluene,2-methyltetrahydrofuran, dioxane, tert.-butyl methylether and anymixture thereof.

The reaction parameters for step (a-VI), such as, for example, pressure,temperature or reaction time, can vary over a wide range. It ispreferable if the reaction temperature in step (a-VI) is between 15 and100° C., particularly preferably between 18 and 80° C. Preferably, step(a-VI) is carried out at normal pressure.

The reaction time can vary depending on various parameters, such as, forexample, temperature, pressure, nature of the compound to be reacted andcan be determined for the process in question by persons skilled in theart using preliminary tests. It is preferable if the reaction time ofstep (a-VI) is between 2 and 25 h, particularly preferably between 3 and22 h, more particularly preferably between 4 and 20 h.

The deprotected compound according to formula (Ib) can be isolatedand/or purified by conventional methods known to persons skilled in theart.

Optionally, the compound according to formula (Ib) may be converted intoa physiologically acceptable acid addition salt thereof according to theprocedure previously described for step (a-III).

Step (a-VII)

In a preferred embodiment of the process of the invention, alternative Afurther comprises a step (a-VII-1) or (a-VII-2) for the preparation of acompound according to formula (A-0) as depicted in Scheme A4 below:

In step (a-VII-1) a magnesium halide, i.e. a Grignard reagent is formedfrom a compound according to formula (A-01), wherein Hal is a halogenatom, preferably selected from the group consisting of Cl, Br and I, inparticular Br, and magnesium in an inert reaction medium. Said Grignardreagent is then reacted with a compound according to formula (A-02)under Grignard conditions in an inert reaction medium, preferably in anorganic ether, for example, selected from the group consisting ofdiethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,tert-butylmethyl ether or any mixture thereof to obtain a compoundaccording to formula (A0).

Alternatively, in step (a-VII-2) a compound according to formula (A-03)is reacted with ethyl magnesium halide, preferably ethyl magnesiumbromide or ethyl magnesium chloride, in an inert reaction medium,preferably in an organic ether, for example, selected from the groupconsisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,tert-butylmethyl ether or any mixture thereof under Grignard conditions,optionally in the presence of at least one Lewis acid, preferably atleast one Lewis acid selected from the group consisting of AlCl₃ andcerium(III) chloride (CeCl₃), more preferably CeCl₃ to obtain a compoundaccording to formula (A0). The reaction is particularly preferablycarried out in tetrahydrofuran with ethyl magnesium chloride at aconcentration from 0.5 M to 2 M of the ethyl magnesium chloride.Particularly preferably the reaction is carried out at a concentrationof 1 M or 2 M of the ethyl magnesium chloride.

The particular compound of general formulas (A-0) obtained can beisolated and/or purified by conventional methods known to personsskilled in the art.

Process According to Alternative B

The process of the invention according to alternative B comprises atleast the step (b-I), i.e. a conversion of a compound according toformula (B-I), wherein R³ has one of the above defined meanings, into acompound according to formula (I), wherein R¹, R² and R³ in each casehave one of the above defined meanings as depicted in Scheme B1 below:

Step (b-I)

Preferably, step (b-I) is a reductive amination of a compound accordingto formula (B-I) to a compound according to formula (I) and is performedin the presence of H—NR¹R² and/or a salt thereof as amine component,wherein R¹ and R² have one of the above defined meanings, preferablyboth denote a methyl group, and at least one reducing agent. Anyreducing agent suitable for the reduction amination of a compoundbearing a carbonyl group such as an aldehyde group to a compound bearingan amine group may be employed. Preferably, the suitable reducing agentis at least one metal hydride, more preferably at least one metalhydride selected from the group consisting of sodium tetrahydridoborate(NaBH₄) and sodium trihydridocyanoborate (NaBH₃(CN)), in particularsodium trihydridocyanoborate. However, it is also possible to employ ametal such as iron, zinc or tin in combination with at least one acid,preferably at least one acid selected from the group consisting ofacetic acid, hydrochloric acid and hydrobromic acid as reducing agent.Further, hydrogen in combination with a catalyst, preferably incombination with a heterogeneous catalyst may be employed as a suitablereducing agent. Moreover, a combination of formic acid and formaldehydemay be employed as a suitable reducing agent.

Most preferably, the suitable reducing agent is a combination of formicacid and formaldehyde. Such a combination of formic acid andformaldehyde has the advantage that—if R³ in formula (B-I) denotes H,the resulting OH-group at the aromatic moiety of formula (B-I) will notbe deprotonated. Further, by employing a combination of formic acid andformaldehyde as a suitable reducing agent, a compound of (I) will beobtained, wherein R¹ and R² both denote methyl.

Preferably, in step (b-I) the reducing agent, is dissolved or suspendedin a suitable reaction medium together with the amine component and/or asalt thereof and then the compound according to formula (B-I), which ispreferably dissolved in a suitable solvent, is added to the solution orsuspension comprising the reducing agent and the amine component and/ora salt thereof.

Suitable solvents for the compound according to formula (B-I) arepreferably selected from the group consisting of methanol, ethanol,isopropanol, 1,4-dioxane, tetrahydrofuran (THF) and any mixture in anyratio thereof. A particularly preferred solvent is methanol.

Suitable reaction media for dissolving or suspending the reducing agentand the amine component and/or a salt thereof are preferably selectedfrom the group consisting of methanol, ethanol, n-propanol, isopropanol,1,4-dioxane, tetrahydrofuran (THF) and any mixture in any ratio thereof.A particularly preferred reaction medium is methanol.

The reaction parameters for the reduction in step (b-I) such as, forexample, pressure, temperature or reaction time, can independently ofanother vary over a wide range. Preferably, the temperature in step(b-I) is in each case from 0 to 250° C., particularly preferably from 15to 180° C. and very particularly preferably from 15 to 80° C. Thereduction in step (b-I) can preferably be carried out at reducedpressure, at normal pressure or at elevated pressure, preferably in therange from 0.5 to 300 bar. It is particularly preferred to carry out thereactions under pressure in a range from 0.5 to 10 bar, in particularfrom 0.75 to 5 bar. The reaction time can vary in dependence on variousparameters, such as, for example, temperature, pressure, nature of thecompound to be reacted or the properties of the catalyst, and can bedetermined for the process in question by persons skilled in the artusing preliminary tests.

The particular compound of formula (I) obtained in step (b-I) can beisolated and/or purified by conventional methods known to personsskilled in the art.

Step (b-II)

Optionally, the compound according to formula (I) may be converted intoa physiologically acceptable acid addition salt thereof in step (b-II).The conversion of a compound according to formula (I) into acorresponding acid addition salt may be carried out has it has beenpreviously described in step (a-III) according to alternative A of theprocess of the invention.

Step (b-III)

In a particularly preferred embodiment of the process of the invention,alternative B further comprises a deprotection step (b-III), wherein thecompound according to formula (I), wherein R¹ and R² have in each casehave one of the above defined meanings and R³ in each case is ≠H, isdeprotected to obtain a compound according to formula (Ib). Preferably,the deprotection step (b-III) is carried out as it has been previouslydescribed in step (a-VI) according to alternative A of the process ofthe invention.

Step (b-IV)

In a preferred embodiment of the process of the invention, alternative Bfurther comprises a step (b-IV) for the preparation of a compoundaccording to formula (B-I) as depicted in the following Scheme B2:

Preferably, step (b-IV) is an 1,4-addition reaction of anα,β-unsaturated carbonyl compound (B-0-II) and a compound according toformula (B-0-I).

In a preferred embodiment of step (b-IV) a metal halide, preferably amagnesium halide, is first formed from a compound according to formula(B-0-I), wherein Hal is a halogen atom, preferably selected from thegroup consisting of Cl, Br and I, in particular Br, and a metal,preferably magnesium to form a Grignard reagent, in an inert reactionmedium. Suitable reaction media for producing said metal halide arepreferably selected from the group consisting of diethyl ether,diisopropyl ether, 1,4-dioxane, tetrahydrofuran (THF) and any mixturesin any ratio thereof. A particularly preferred reaction medium is THF.The thus obtained metal halide is then converted into an organocoppercompound by reaction with a suitable copper precursor compound,preferably a copper(I)-compound, more preferably selected from the groupconsisting of copper(I) halides, in particular copper(I) iodide,copper(I) bromide or copper(I) chloride, and copper(I) cyanide. The thusobtained organocopper compound is then reacted with a compound (B-0-II),preferably dissolved or suspended in a suitable reaction medium,preferably selected from the group consisting of diethyl ether,diisopropyl ether, 1,4-dioxane, tetrahydrofuran (THF) and any mixture inany ratio thereof to obtain a compound according to formula (B-I).

In another preferred embodiment of step (b-IV), an organometal compound,preferably an organolithium compound, is first formed from a compoundaccording to formula (B-01), wherein Hal is a halogen atom, preferablyselected from the group consisting of Cl, Br and I, in particular Br,and a suitable organometallic precursor compound, preferably anC₁₋₄-alkyl lithium compound, more preferably n-butyl lithium in an inertreaction medium. Suitable reaction media for producing said organometalcompound are preferably selected from the group consisting of diethylether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran (THF) and anymixtures in any ratio thereof. A particularly preferred reaction mediumis THF. The thus obtained organometal compound is then converted into anorganocopper compound by reaction with a suitable copper precursorcompound, preferably a copper(I)-compound, more preferably selected fromthe group consisting of copper(I) halides, in particular copper(I)iodide, copper(I) bromide or copper(I) chloride, and copper(I) cyanide.The thus obtained organocopper compound is then reacted with a compound(B-0-II), preferably dissolved or suspended in a suitable reactionmedium, preferably selected from the group consisting of diethyl ether,diisopropyl ether, 1,4-dioxane, tetrahydrofuran (THF) and any mixture inany ratio thereof to obtain a compound according to formula (B-I).

The particular compound of formula (B-I) obtained in step (b-IV) can beisolated and/or purified by conventional methods known to personsskilled in the art.

Process According to Alternative C

The process of the invention according to alternative C comprises atleast the step (c-I), i.e. hydrogenation of a compound according toformula (C-I) to a compound according to formula (C-II) (step c-I),wherein R³ in each case has one of the above defined meanings, andoptionally converting the thus obtained compound of formula (C-II) intoa physiologically acceptable acid addition salt thereof (step c-II) oroptionally converting the resulting compound of formula (C-II) into acompound according to formula (I), and optionally converting the thusobtained compound according to formula (I) into a physiologicallyacceptable acid addition salt thereof. Steps (c-I) and (c-III) aredepicted in the following Scheme C1:

Step (c-I)

Preferably, the hydrogenation step (c-I) of the process of the inventionaccording to alternative C is effected via heterogeneous or homogeneouscatalysis, in each case in the presence of hydrogen. The hydrogenemployed is preferably in gaseous form or at least part of it isdissolved in a liquid phase. In particular, the hydrogenation step (c-I)of the process of the invention according to alternative A is effectedvia heterogeneous catalysis.

If a homogeneous catalyst in hydrogenation step (c-I) according toalternative C of the process of the invention is employed, the samehomogeneous catalysts as well as the same reaction parameters may beapplied which may be also used for the hydrogenation reaction of step(a-I) of alternative A of the process of the invention.

If a heterogeneous catalyst in hydrogenation step (c-I) according toalternative C of the process of the invention is employed, the sameheterogeneous catalysts as well as the same reaction parameters may beapplied which may be also used for the hydrogenation reaction of step(a-I) of alternative A of the process of the invention.

In particular, a heterogeneous catalyst is employed in hydrogenationreaction step (c-I) in alternative C of the process of the invention.Preferred heterogeneous catalysts employed in this step are eachindependently selected from the group consisting of Raney nickel,palladium, palladium on carbon (1-10 wt. %, preferably 5 wt. %),platinum, platinum on carbon (1-10 wt. %, preferably 5 wt. %), rutheniumon carbon (1-10 wt. %, preferably 5 wt. %) and rhodium on carbon (1-10wt. %, preferably 5 wt. %). Most preferred is Raney Nickel as thecatalyst for hydrogenation in step (c-I).

The compound according to formula (C-I) according to the process of theinvention is preferably in liquid phase and to that end are preferablymixed with or dissolved in a reaction medium that is liquid under theparticular reaction conditions. Examples of suitable reaction mediaemployed in hydrogenation reactions are methanol, ethanol, isopropanol,n-butanol, n-propanol, toluene, n-heptane, n-hexane, n-pentane, aceticacid, ethyl acetate, formic acid, hydrochloric acid, hydrobromic acid,sulfuric acid and mixtures thereof. More preferably methanol is used asthe reaction medium in step (c-I). Of course, it is also possible to usemixtures or multiphase systems comprising two or more of theabove-mentioned liquids in the processes according to the presentinvention.

The reaction parameters for the hydrogenation reaction via heterogeneouscatalysis in step (c-I) such as, for example, pressure, temperature orreaction time, can independently of another vary over a wide range both.Preferably, the temperature during the heterogeneous hydrogenation instep (c-I) is in each case from 0 to 250° C., particularly preferablyfrom 15 to 180° C. and very particularly preferably from 15 to 30° C.The heterogeneous hydrogenation in step (c-I) can preferably be carriedout at reduced pressure, at normal pressure or at elevated pressure,preferably in the range from 0.5 to 300 bar. It is particularlypreferred to carry out the reactions under pressure in a range from 0.5to 10 bar, in particular from 0.75 to 10 bar. The reaction time can varyin dependence on various parameters, such as, for example, temperature,pressure, nature of the compound to be reacted or the properties of thecatalyst, and can be determined for the process in question by personsskilled in the art using preliminary tests.

The continuous removal of samples in order to monitor the reaction, forexample by gas chromatography (GC) methods, is also possible, optionallyin combination with regulation of the corresponding process parameters.

The total amount of the heterogeneous catalyst(s) used depends onvarious factors, such as, for example, the ratio of the catalyticallyactive component to any inert material present, or the nature of thesurface of the catalyst(s). The optimal amount of catalyst(s) for aparticular reaction can be determined by persons skilled in the artusing preliminary tests.

The particular compound of formula (C-II) obtained in step (c-I) can beisolated and/or purified by conventional methods known to personsskilled in the art.

Step (c-II)

The compound according to formula (C-II) obtained in step (c-I)corresponds to a compound according to formula (I), wherein R¹ and R²both denote H.

Optionally, the compound according to formula (C-II) may be convertedinto a physiologically acceptable acid addition salt thereof in step(c-II).

The conversion of a compound according to formula (C-II) into acorresponding acid addition salt may be carried out has it has beenpreviously described for the conversion of a compound according toformula (I) into a physiologically acceptable acid addition salt thereofin step (a-III) according to alternative A of the process of theinvention.

Step (c-III)

Optionally, the compound according to formula (C-II) may be convertedinto a compound according to formula (I) in step (c-III), i.e. in acompound according to formula (I), wherein at least one of R¹ and R²denotes a C₁₋₄-aliphatic residue.

Any method suitable for substituting at least one hydrogen atom of aprimary amine group with a C₁₋₄-aliphatic residue may be performed instep (c-III).

In a preferred embodiment, a compound according to formula (C-II) may besubjected to a reaction with a compound halogen substitutedC₁₋₄-aliphatic compound, preferably a halogen substituted C₁₋₄-alkylcompound (C₁₋₄-alkyl-Hal), wherein Hal in each case is preferablyselected from the group consisting of Cl, Br and I to obtain a compoundaccording to formula (I), wherein at least one of R¹ and R² denotes aC₁₋₄-aliphatic residue.

In another preferred embodiment, a compound according to formula (C-II)may be subjected to an Eschweiler-Clarke reaction in step (c-III).Preferably, a compound according to formula (C-II) is reacted withformaldehyde or a formaldehyde source such as paraformaldehyde, therebygenerating a corresponding imine compound which is then further reactedwith an acid, preferably an organic acid, more preferably, formic acid,thereby generating a compound according to formula (I), wherein at leastone of R¹ and R² denotes a C₁₋₄-aliphatic residue, preferably both R¹and R² denote a C₁₋₄-aliphatic residue, even more preferably both R¹ andR² denote a methyl group. Alternatively, a compound according to formula(C-II) is reacted with formaldehyde or a formaldehyde source such asparaformaldehyde, thereby generating a corresponding imine compoundwhich is then further reacted with an hydrogen in combination with acatalyst, thereby generating a compound according to formula (I),wherein at least one of R¹ and R² denotes a C₁₋₄-aliphatic residue,preferably both R¹ and R² denote a C₁₋₄-aliphatic residue, even morepreferably both R¹ and R² denote a methyl group.

Optionally, the thus obtained compound according to formula (I) may thenbe converted into a physiologically acceptable acid addition saltthereof, as has it has been previously described in step (a-III)according to alternative A of the process of the invention.

Steps (c-IV) and (c-V)

In a preferred embodiment of the process of the invention, alternative Cfurther comprises a step (c-IV), wherein a compound of formula (C-0-I)is subjected to a desilylation reaction, wherein R³ is selected from thegroup consisting of H and a C₁₋₄-aliphatic residue, and wherein R^(a),R^(b) and R^(c) are independently selected from the group consisting ofC₁₋₈-aliphatic residues and aryl, preferably independently of anotherdenote a C₁₋₈-aliphatic residue, even more preferably each denotemethyl,

yielding a compound according to formula (C-0-II), wherein R³ has theabove defined meaning,

and a step (c-V), wherein a compound of formula (C-0-II) is subjected toa dehydration reaction yielding the compound according to formula (C-I).Steps (c-IV) and (c-V) are depicted in the following Scheme C2:

In a preferred embodiment of the present invention, the compoundaccording to formula (C-0-II) is not isolated, i.e. a compound accordingto formula (C-0-I) can be directly transformed into a compound accordingto formula (C-I) in one step, i.e. steps (c-IV) and (c-V) can be carriedout in one step (c-IV-V).

The desilylation step (c-IV) is preferably acid-catalyzed oracid-promoted or performed in the presence of a fluoride source such aspotassium fluoride or cesium fluoride or tributylammonium fluoride.Alternatively, in case R^(a), R^(b) and R^(c) each denote methyl, (c-IV)may also be performed in the presence of a base, preferably an inorganicbase such as potassium carbonate. However, in a most preferredembodiment desilylation step (c-IV) is performed in the presence of anacid in a catalytically effective or at least stoichiometric amount.Preferably the acid is selected from the group consisting of formicacid, hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid,methanesulfonic acid, phosphoric acid or any mixture thereof. It ispreferable if the acid is employed in a high concentration. Particularlypreferably, hydrochloric acid is employed.

Examples of suitable reaction media for (c-IV) include lower alcoholssuch as methanol or ethanol as well as THF, 1,4-dioxane or any mixturethereof. Of course, it is also possible to use mixtures or multiphasesystems comprising two or more of the above-mentioned liquids in theprocesses according to the present invention.

The particular compound of general formula (C-0-II) obtained can beisolated and/or purified by conventional methods known to personsskilled in the art

The dehydration step (c-V) is preferably acid-catalyzed oracid-promoted, i.e. performed in the presence of an acid in acatalytically effective or at least stoichiometric amount. Preferablythe acid is selected from the group consisting of formic acid,hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid,methanesulfonic acid, p-toluenesulfonic acid, phosphorous pentoxide,thionyl chloride, phosphoryl chloride or any mixture thereof. It ispreferable if the acid is employed in a high concentration. Particularlypreferably, phosphoryl chloride is employed.

The compound of general formula (C-0-II) used in step (c-V) according tothe present invention is preferably in liquid phase and to that end ispreferably mixed with or dissolved in a reaction medium that is liquidunder the particular reaction conditions.

Examples of suitable reaction media include acetic acid, formic acid,toluene, pyridine, hydrochloric acid, sulfuric acid, hydrobromic acid,methanesulfonic acid, p-toluenesulfonic acid, phosphorous pentoxide,thionyl chloride, phosphoryl chloride or any mixture thereof. Of course,it is also possible to use mixtures or multiphase systems comprising twoor more of the above-mentioned liquids in the processes according to thepresent invention. Preferably, step (c-V) is performed in pyridine as areaction medium in the presence of phosphoryl chloride.

The reaction parameters for step (c-V), such as, for example, pressure,temperature or reaction time, can vary over a wide range. It ispreferable if the reaction temperature in step (c-V) is between 15 and100° C., particularly preferably between 18 and 90° C. The dehydrationstep (c-V) can preferably be carried out at reduced pressure, at normalpressure or at elevated pressure, preferably in the range from 0.01 to300 bar. It is particularly preferred to carry out the reaction underpressure in a range from 0.5 to 5 bar, in particular from 0.5 to 1.5bar.

The reaction time can vary depending on various parameters, such as, forexample, temperature, pressure, nature of the compound to be reacted orthe properties of the catalyst, and can be determined for the process inquestion by persons skilled in the art using preliminary tests.Preferably, the reaction time of step (c-V) is between 2 and 25 h,particularly preferably between 3 and 22 h, more particularly preferablybetween 4 and 20 h.

The continuous removal of samples in order to monitor the reaction, forexample by means of gas chromatographic (GC) methods, is also possible,optionally in combination with regulation of the corresponding processparameters.

The particular compound of general formula (C-I) obtained can beisolated and/or purified by conventional methods known to personsskilled in the art.

Step (c-VI)

In a particularly preferred embodiment of the process of the invention,alternative C further comprises a deprotection step (c-VI), wherein oneof the compounds according to formula (C-I), (C-II), (C-0-I), (C-0-II)or (I), wherein R¹ and R² have in each case have one of the abovedefined meanings and R³ in each case is ≠H, is deprotected to obtain acompound according to formula (Ib). Preferably, the deprotection step(c-VI) is carried out by subjecting a compound according to formula (I),(C-I), or (C-II), more preferably a compound according to formula (C-I),to said deprotection.

Preferably, at least one acid, preferably at least one acid selectedfrom the group consisting of hydrobromic acid, hydrochloric acid andmethanesulfonic acid is employed as deprotecting agent in step (c-VI).In case methanesulfonic acid is employed as acid a combination ofmethanesulfonic acid and methionine is preferably used as asdeprotecting agent. A combination of methanesulfonic acid and methionineis the most preferred deprotecting agent in step (c-VI). Thedeprotection step (c-VI) is preferably carried out in a reaction mediumselected from the group consisting of diethylether, tetrahydrofuran,toluene, 2-methyltetrahydrofuran, dioxane, tert.-butyl methylether andany mixture thereof.

The reaction parameters for step (c-VI), such as, for example, pressure,temperature or reaction time, can vary over a wide range. It ispreferable if the reaction temperature in step (c-VI) is between 15 and100° C., particularly preferably between 18 and 80° C. Preferably, step(c-VI) is carried out at normal pressure.

The reaction time can vary depending on various parameters, such as, forexample, temperature, pressure, nature of the compound to be reacted andcan be determined for the process in question by persons skilled in theart using preliminary tests. It is preferable if the reaction time ofstep (c-VI) is between 2 and 25 h, particularly preferably between 3 and22 h, more particularly preferably between 4 and 20 h.

The particular deprotected compound of formula (Ib) can be isolatedand/or purified by conventional methods known to persons skilled in theart.

Step (c-VII)

In a preferred embodiment of the process of the invention, alternative Cfurther comprises a step (c-VII) for the preparation of a compoundaccording to formula (C-0-I) as depicted in the following Scheme C4:

In step (c-VII) a compound according to formula (C-0-III), wherein R³has one of the above defined meanings, is reacted with a compound havingthe formula SiR^(a)R^(b)R^(c)(CN), wherein R^(a), R^(b) and R^(c) areeach independently selected from the group consisting of C₁₋₈-aliphaticresidues and aryl, preferably independently of another denote aC₁₋₈-aliphatic residue. Preferably the compound SiR^(a)R^(b)R^(c)(CN) isselected from the group consisting of trimethylsilylcyanide,triethylsilylcyanide, tri-n-propylsilylcyanide andtriisopropylsilylcyanide. Most preferred is trimethylsilylcyanide.

A suitable reaction medium for step (c-VII) is preferably at least onereaction medium selected from the group consisting of acetone, benzene,n-butanol, 2-butanone, tert.-butyl methylether, chloroform, cyclohexane,diethyl ether, 1,4-dioxane, diisopropyl ether, alkyl acetates, e.g.ethyl acetate, ethanol, n-hexane, n-heptane, isopropanol, methanol,methylene chloride (dichloromethane), n-pentane, petrol ether,n-propanol, tetrahydrofuran, toluene and any mixture in any mixing ratiothereof. Most preferred reaction media are n-hexane and n-heptane.

Preferably, step (c-VII) of the process of the invention according toalternative C is performed in the presence of at least metal halide,preferably at least one transition metal halide, wherein the halide ispreferably selected from the group consisting of chloride, bromide andiodide. Most preferred is a zinc halide, in particular zinc iodide(ZnI₂).

The thus obtained compound according to formula (C-0-I) of can beisolated and/or purified by conventional methods known to personsskilled in the art.

Any stereoisomers of any compounds obtained via alternatives A, B or Cof the process of the invention, such as e.g. a compound according toany of the formulas (I-1), (I-2), (I-3), (I-4), (I-1a), (I-2a), (I-3a),(I-4-a), (PI-1), (PI-2), (PI-3) and (PI-4) may be separated from eachother at any time of each reaction sequence and/or purified byconventional methods known to a person skilled in the art. Preferably,LC (liquid chromotography) techniques, more preferably HPLC (highperformance liquid chromatography) techniques, even more preferablysemi-preparative or preparative HPLC techniques may be used for theseparation of these stereoisomers. Alternatively, fractionizedcrystallization of any mixture of these stereoisomers may be carried outto separate any unwanted stereoisomers.

The steps according to each of the three alternatives according to thepresent invention can be carried out discontinuously (batchwise) orcontinuously, preference being given to the discontinuous procedure.

There come into consideration as the reactor for the discontinuousprocedure, for example, a slurry reactor, and for the continuousprocedure a fixed-bed reactor or loop reactor.

EXAMPLES

In the following, the present invention is illustrated by a number ofexamples for each of the alternatives A to C of the process of theinvention. The examples are only illustrative do not limit the scope ofthe invention.

ABBREVIATIONS USED IN THE EXAMPLES

-   -   AIBN: azo-bis-isobutyronitrile    -   AlCl₃: aluminium chloride    -   Eq.: equivalents    -   CC: column chromatography on silica gel    -   DCC: N,N′-dicyclohexyl carbodiimide    -   THF: tetrahydrofuran    -   TEA: triethylamine    -   h: hour(s)    -   HPLC: high performance liquid chromatography    -   HBr: hydrobromic acid    -   HCl: hydrochloric acid    -   MgSO₄: magnesium sulfate    -   NH₄HSO₄: ammonium hydrogen sulfate    -   NaOH: sodium hydroxide    -   NaCl: sodium chloride    -   NaHCO₃: sodium hydrogen carbonate    -   Na₂CO₃: sodium carbonate    -   KOtBu: potassium tert-butylate    -   LAH: lithium aluminium hydride    -   HOBT (1-HBT): 1-hydroxybenzotriazol    -   RT: room temperature    -   TMSCN: trimethylsilylcyanide    -   TBAB: tetra-n-butylammoniumbromide    -   GC-MS: gas chromatographic/mass spectrometric analysis

“M” and “N” are concentrations in mol/l. “%” is wt.-% unless indicatedotherwise. The yields of any compounds obtained in any steps of theprocess of the invention have not been optimized. Any temperatures werenot corrected.

All compounds not explicitly described were either commerciallyavailable (e.g. from Acros, Avocado, Aldrich, Bachem, Fluke, Lancaster,Maybridge, Merck, Sigma, TCI, Oakwood etc.) (syntheses of thesecompounds may e.g. be researched in the “Symyx® Available ChemicalsDatabase” of the company MDL, San Ramon, US) or the syntheses of thesecompounds has been already described by technical literature sources(experimental procedures may e.g. by researched in the “Reaxys®”database of the company Elsevier, Amsterdam, NL) or these compounds maybe synthesized according to conventional procedures known to a personskilled in the art.

Silica gel 60 (0.010-0.063 mm; company: Merck, Darmstadt, Germany) wasused as stationary phase for CC (column chromatography). Mixing ratiosof any solvent or eluent mixtures are indicated in volume/volume. Theanalytical characterization of all compounds was performed by means of¹H-NMR spectroscopy and mass spectrometric analyses.

A process according to alternative A for the preparation of differentstereoisomers of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol isdepicted in the following Scheme A:

Step a1a: compound A2 (N,N-2-trimethyl-3-oxopentanamide)

32.1 ml (0.35 mol) phosphoryl trichloride (POCl₃) were dissolved in 100mL of toluene. 32.6 ml (0.3 mol) N,N-dimethylpropionamide (A1)(dissolved in 50 mL toluene) were added to the resulting solution understirring under an inert gas atmosphere. The reaction mixture was heatedto 80° C. for 6 h, allowed to cool to RT and stirred for another 12 h atRT. After evaporation of toluene under reduced pressure, the resultingmixture was stirred for 2 h. 100 mL toluene were then added, theresulting mixture was cooled to below 0° C. and icy water (100 mL) wasadded. Then, 24 g of solid NaOH, dissolved in water, were added to themixture. After 1 h of stirring, 47.7 g Na₂CO₃ as solid were added andthe resulting mixture was stirred for 16 h at RT. The organic layer wasseparated, dried over MgSO₄ and distilled (0.8 bar, 78-82° C.). 10.8 g(46%) of A2 was obtained in form of a colorless solid.

Step a2a: compounds A3a and A3b((2RS,3SR)-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

To 699 mg (29 mmol) of magnesium 20 mL of dry THF were added. A solutionof 3.64 mL of 3-bromoanisole in 10 mL of dry THF was slowly addeddropwise. After addition, the remaining suspension was refluxed for 2 hand then cooled to 0° C. 7.1 g (29 mmol) of anhydrous cerium (III)chloride were dissolved in 65 mL of dry THF and added to the reactionmixture which was then stirred for 90 minutes at 0° C. 3 g (19 mmol) ofA2 (dissolved in 10 mL dry THF) were slowly added dropwise. After 1 hthe reaction mixture was hydrolyzed by an aqueous saturated solution ofNaHCO₃ at 10-15° C. The organic layer was separated and the aqueouslayer was extracted with diethyl ether three times. The combined organiclayers were dried over MgSO₄. The organic solvents were evaporated underreduced pressure and the remaining residue was dried in vacuo. CC(eluent: n-hexane/diethyl ether (1:4)) yielded 3.29 g (65%) of A3a andA3b in form of a yellowish oil.

Step a1b: compound A5(3-(3-methoxyphenyl)-N,N,2-trimethyl-3-oxopropanamide)

To 2,2,6,6-tetramethylpiperidine (17.5 g, 125 mmol) in 50 ml dry THFwere added dropwise 72 ml (115 mmol) of a n-buthyllithium solution inn-hexane (1.6 M) at −30° C. After 30 minutes of stirring, 5.0 g (50mmol) N,N-dimethylpropionamide (A1) (dissolved in 50 mL dry THF) wereadded and the mixture was cooled to −70° C. and stirred for 1 h at thistemperature. 22.5 g (125 mmol) ethyl-3-methoxybenzoate (dissolved in 30mL dry THF) were slowly added dropwise and the resulting mixture wasstirred for another 2 h at −70° C. After the mixture had been allowed towarm to RT, it was hydrolyzed by employing a diluted aqueous solution ofHCl (36 mL). The mixture was then washed with diethyl ether severaltimes. The combined organic layers were dried over MgSO₄. The organicsolvents were evaporated under reduced pressure and the remainingresidue was dried in vacuo. CC (eluent: n-hexane/ethyl acetate (1:4))yielded 6.5 g (55%) of A5 in form of a colorless oil.

Step a2b: compounds A3c and A3d((2RS,3RS)-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

2.4 g (6.4 mmol) anhydrous cerium (III) chloride were dissolved in 22 mLof dry THF. 2.13 mL (6.4 mmol) of a solution of ethyl magnesium bromidein diethyl ether (3 M) were added to the resulting solution at 0° C. andthe mixture was stirred for 90 minutes at this temperature.

1 g (4.3 mmol) of A2 (dissolved in 5 mL dry THF) were slowly addeddropwise. After 1 h of stirring the reaction mixture was hydrolyzed byemploying an aqueous saturated solution of NaHCO₃ at 10-15° C. Theorganic layer was separated and the aqueous layer was extracted withdiethyl ether three times. The combined organic layers were dried overMgSO₄. The organic solvents were evaporated under reduced pressure andthe remaining residue was dried in vacuo. CC (eluent: n-hexane/diethylether (1:1)) yielded 740 mg (66%) of A3c and A3d in form of a yellowishoil.

Step a3a: compound A6(Z,E-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide

3.25 g (12 mmol) A3a and A3b were dissolved in 35 mL of an aqueoussolution of HBr (47%) and stirred for 20 h. The reaction mixture wasthen cooled to 0° C. 50 mL of ethyl acetate and 50 mL of water wereadded and the resulting mixture was alkalized with solid NaHCO₃. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate several times. The combined organic layers were dried overMgSO₄. The organic solvent was evaporated under reduced pressure and theremaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether(1:1)) yielded 1.61 g (54%) of A6 in form of a colorless oil.

Step a3b: compound A6(Z,E-3-hydroxy-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide

3.25 g (12 mmol) A3c and A3d were dissolved in 35 mL of an aqueoussolution of HBr (47%) and stirred for 20 h. The reaction mixture wasthen cooled to 0° C. 50 mL of ethyl acetate and 50 mL of water wereadded and the resulting mixture was alkalized with solid NaHCO₃. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate several times. The combined organic layers were dried overMgSO₄. The organic solvent was evaporated and the remaining residue wasdried in vacuo. CC (eluent: n-hexane/diethyl ether (1:1)) yielded 2.68 g(90%) of A6 in form of a colorless oil.

Step a4: compound A7 (Z,E-3-(3-methoxyphenyl)-N,N,2-trimethylpent-2-enamide)

700 mg (2.8 mmol) A6 were dissolved in 20 mL of dry THF. 318 mg (2.8mmol) KOtBu were added to the resulting solution. The resulting mixturewas refluxed for 3 h. After cooling to RT 50 mL of ethyl acetate and 50mL of water were added. The layers of the resulting solution wereseparated and the aqueous layer was extracted twice with ethyl acetate.The combined organic layers were dried over MgSO₄. The organic solventwas evaporated under reduced pressure and the remaining residue wasdried in vacuo. CC (eluent: n-hexane/diethyl ether (1:1)) yielded 430 mg(61%) of A7 in form of a colorless oil.

Step a5: compounds A8a and A8b((2RS,3RS)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

400 mg (1.6 mmol) A7 were placed in a hydrogenation apparatus anddissolved in 10 mL of methanol. 1 drop of concentrated HCl and a smallamount of mg Pd/C (10% Pd) covering the tip of a spatula as catalystwere added under inert gas atmosphere. The resulting mixture washydrogenated at room temperature under a H₂-pressure of 1 bar for 6 h(91 mL H₂ were used). The solids were filtered off and washed withmethanol. The methanol portion and the filtrate were combined. Afterevaporation of the organic solvents, the residue was suspended in amixture of water and diethyl ether (30 mL each). A diluted aqueoussolution of NaOH was added to the mixture until alkalization. The layersof the resulting solution were separated and the aqueous layer waswashed three times with diethyl ether. The combined organic layers weredried over MgSO₄. The organic solvent was evaporated under reducedpressure and the remaining residue was dried in vacuo. CC (eluent:n-hexane/diethyl ether (1:1)) yielded 160 mg (45%) of A8a and A8b inform of a colorless oil. As a side product, A8c and A8d could beobtained in a yield of 25% (80 mg) in form of a colorless oil.

Step e0: compounds A8a and A8b((2RS,3RS)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

200 mg (0.8 mmol) of a mixture of A8c and A8d were dissolved in 4 mL ofdry THF. 90 mg (0.8 mmol) KOtBu were added to the resulting solution.The resulting mixture was refluxed for 3 h. After cooling to RT 50 mL ofethyl acetate and 50 mL of water were added. The layers of the resultingsolution were separated and the aqueous layer was extracted twice withethyl acetate. The combined organic layers were dried over MgSO₄. Theorganic solvent was evaporated under reduced pressure and the remainingresidue was dried in vacuo yielding a mixture of A8a/A8b and thestarting material A8c/A8d (GC-MS: 1:4) in form of a yellowish oil.

Step a6: compounds A9a and A9b((2RS,3RS)₃-(3-hydroxyphenyl)-N,N,2-trimethylpentanamide)

To 202 mg D,L-methionine (1.4 mmol) and 2 mL methane sulfonic acid wereadded 170 mg (0.68 mmol) of A8a and A8b. The reaction mixture wasstirred for 6 h. Water and ethyl acetate (20 mL each) were added. Afterneutralization with solid NaHCO₃ the layers were separated from eachother. The aqueous layer was extracted twice with ethyl acetate. Thecombined organic layers were dried over MgSO₄. The organic solvents wereevaporated under reduced pressure and the remaining residue was dried invacuo. 160 mg (99%) of A9a and A9b were obtained in form of a colorlessoil.

Step a7: compounds 1a and 1b((2R,S,3RS)-3-(1-(dimethylamino)-2-methylpentan-3-yl)-phenol)

To 1.6 mL (0.35 mmol) of LAH-THF solution (2.3 M) were added 120 mg(0.90 mmol) of AlCl₃. The resulting mixture was stirred for 45 minutesat RT. 170 mg (0.72 mmol) of A9a and A9b (dissolved in 5 ml of dry THF)were added to the mixture at RT. The resulting mixture was then refluxedfor 1 h. Then the reaction mixture was hydrolyzed by addition of 20 mLof an aqueous solution of NaHCO₃ (10%). 20 mL of diethyl ether wereadded and the layers were separated from each other and the aqueouslayer was extracted twice with diethyl ether. The combined organiclayers were dried over MgSO₄. The organic solvent was evaporated underreduced pressure and the remaining residue was dried in vacuo. 1a and 1bwere obtained in form of a colorless oil. The hydrochloride salts of 1aand 1b were obtained by addition of trimethylsilylchloride (76 μl) to asolution of 1a and 1b in acetone (yield: 100 mg (54%) in form of acolorless solid).

Step a8: compound A8c and A8d((2RS,3SR)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamide)

1 g (4 mmol) A6 were placed in a hydrogenation apparatus and dissolvedin 10 mL of methanol. 1 drop of concentrated HCl and 250 mg Pd/C (10%Pd) as catalyst were added under inert gas atmosphere. The resultingmixture was hydrogenated at room temperature under a H₂-pressure of 1bar for 6 h (118 mL H₂ were used). The solids were filtered out andwashed with methanol. The methanol portion and the filtrate werecombined. After evaporation of the organic solvents, the residue wassuspended in a mixture of water and diethyl ether (30 mL each). Dilutedaqueous solution of NaOH was added to the mixture until alkalization.The layers of the resulting solution were separated and the aqueouslayer was washed three times with diethyl ether. The combined organiclayers were dried over MgSO₄. The organic solvent was evaporated and theremaining residue was dried in vacuo. CC (eluent: n-hexane/diethyl ether(1:1)) yielded 1 g (99%) of A8c and A8D as a yellowish oil.

Step a10: compound A9c and A9d((2RS,3SR)-3-(3-hydroxyphenyl)-N,N,2-trimethylpentanamide)

To 170 mg D,L-methionine (1.4 mmol) and 2 mL methane sulfonic acid wereadded 200 mg (0.80 mmol) of A8c and A8d. The reaction mixture wasstirred for 6 h. Water and ethyl acetate (20 mL each) were added. Afterneutralization with solid NaHCO₃ the layers were separated from eachother. The aqueous layer was extracted twice with ethyl acetate. Thecombined organic layers were dried over MgSO₄. The organic solvents wereevaporated under reduced pressure and the remaining residue was dried invacuo. 170 mg (90%) of A9c and A9d were obtained in form of a colorlessoil.

Step a11: compound 1c and 1d((2RS,3SR)-3-(1-(dimethylamino)-2-methylpentan-3-yl)phenol)

To 1.56 mL (0.32 mmol) of LAH-THF solution (2.3 M) were added 113 mg(0.85 mmol) of AlCl₃. The resulting mixture was stirred for 45 minutesat RT. 160 mg (0.68 mmol) of A9c and A9d (dissolved in 5 ml of dry THF)were added to the mixture at RT. The resulting mixture was then refluxedfor 1 h. Then the reaction mixture was hydrolyzed by addition of 20 mLof an aqueous solution of NaHCO₃ (10%). 20 mL of diethyl ether wereadded and the layers were separated from each other and the aqueouslayer was extracted twice with diethyl ether. The combined organiclayers were dried over MgSO₄. The organic solvent was evaporated underreduced pressure and the remaining residue was dried in vacuo. 1c and 1dwere obtained in form of a colorless oil. The hydrochloride salts of 1cand 1d were obtained by addition of trimethylsilylchloride (76 μl) to asolution of 1c and 1d in diethyl ether (yield: 100 mg (54%) in form of acolorless solid).

A process according to alternative B for the preparation of3-(3-methoxyphenyl)-2-methyl-pentyl-dimethylamine is depicted in thefollowing Scheme B:

Step b1: compound B2 (3-(3-methoxyphenyl)-2-methylpentanal)

Alternative a)

To 1.46 g (0.06 mol) of magnesium were added 50 mL of dry THF. 5 dropsof 3-bromoanisole were added to this mixture and the resultingsuspension was refluxed until the reaction started. Then, a solution of7.63 mL of 3-bromoanisole (0.06 mol) in 15 mL of dry THF was slowlyadded dropwise, thereby maintaining a constant reflux of the reactionmixture. After addition and refluxing of the reaction mixture foranother hour, the mixture was cooled to −70° C. At this temperature 11.4g (0.06 mol) copper(I) iodide (CuI) and 30 mL of dry THF were added. Themixture was then allowed to warm to around −65 to −60° C. At thistemperature, commercially available 2-methyl-2-pentenal, dissolved in 15mL of dry THF were added slowly to the reaction mixture. After stirringfor 1 h at −65-−60° C., the reaction mixture was allowed to warm to 0°C. The reaction mixture was hydrolyzed by addition of 50 mL of asaturated aqueous solution of NH₄HSO₄. The mixture was then extractedthree times with 100 mL of diethyl ether. The combined organic layerswere dried over MgSO₄. The organic solvent was evaporated and theremaining residue was dried in vacuo. CC (eluent: diisopropylether/n-hexane (1:30)) yielded 2.3 g (29%) of B2 as a colorless oil.

Alternative b)

10.2 ml 3-bromoanisole (82 mmol) were dissolved in 30 mL of a mixture ofdry diethyl ether/toluene (1:1) and cooled to −70° C. A solution ofn-butyl lithium in n-hexane (55 mL, 1.6 M) was then added to the mixtureand the reaction mixture was stirred for 4 h at this temperature. 3.6 g(80 mmol) of copper(I) cyanide (CuCN) were then added and the mixturewas stirred another 30 minutes at −70° C. 4.6 mL (40 mmol) of pre-cooled2-methyl-2-pentenal and 5.9 mL of a BF₃-diethyl ether-solution (47 mmol)in 30 mL of a mixture of dry diethyl ether/toluene (1:1) were slowlyadded dropwise at this temperature. The reaction mixture was the allowedto warm to RT and stirred or 16 h. 25 mL of a saturated aqueous solutionof NH₄OH were then added and the mixture was extracted with diethylether three times. The combined organic layers were dried over MgSO₄.The organic solvent was evaporated and the remaining residue was driedin vacuo. 8 g (99%) of a colorless oil were obtained which—according toGC-MS analysis—contained 24% of B2.

Step b2: compound 2 (3-(3-ethoxyphenyl)-2-methyl-pentyl-dimethylamine)

To 4.8 mL of a methanolic solution of dimethylamine (9.6 mmol, 2M) wereadded 5 ml of methanol, 0.40 g (4.8 mmol) of dimethylamine hydrochlorideand 0.18 g Na(CN)BH₃ (4.8 mmol). Then, 1 g (4.8 mmol) B2, dissolved in15 ml methanol, were added dropwise and the resulting mixture wasstirred for 20 h at RT. The reaction mixture was poured into 15 mL of acooled aqueous solution of HCl (16%) and extracted with dichloromethane.The layers were separated from each other and the aqueous layer wasalkalized with solid KOH, saturated with NaCl and then extracted withdichloromethane. The dichloromethane layer was separated and dried overMgSO₄. The organic solvents were evaporated under reduced pressure andthe remaining residue was dried in vacuo. 0.21 g (19%) of 2 in form of acolorless oil were obtained.

In Scheme C a process according to alternative C for the preparation of3-(2-(aminomethyl)cyclohexyl)phenol is depicted and described below.

Step c0: compound C1 (3-(3-methoxyphenyl)pentan-2-one)

To 2 mL (13 mmol) of commercially available1-(3-methoxyphenyl)propan-2-one (e.g. from Lancaster)) were added 6.5 mLof an aqueous solution of NaOH (50%), a small amount of TBAB coveringthe tip of a spatula and 1.1 mL (14.1 mmol) of ethyl iodide. Theresulting mixture was stirred for 12 h. After addition of 30 mLdistilled water and 30 mL of toluene, the mixture was stirred foranother hour. The layers were separated and the organic layer was washedwith a saturated aqueous solution of NaCl. The layers were separated andthe organic layer was dried over MgSO₄. The organic solvent wasevaporated under reduced pressure and the remaining residue was dried invacuo. 2.2 g (86%) of C1 were obtained in form of a yellow oil.

Step c1: compound C2(3-(3-methoxyphenyl)-2-methyl-2-(trimethylsilyloxy)pentanenitrile)

To a small amount covering the tip of a spatula of ZnI₂ were added 4.4 g(23 mmol) of C1 and 3.4 mL (25 mmol) TMSCN. The resulting mixture wasstirred for 60 minutes. After addition of 40 mL of dry n-hexane, themixture was refluxed for 15 minutes. After addition of a small amount ofcharcoal covering the tip of a spatula, the resulting mixture wasrefluxed for another 15 minutes. The reaction mixture was then filtered.The solvents of the filtrate were then evaporated under reducedpressure. 6.5 g (97%) of C1 were obtained in form of a grey oil.

Step c2: compound C3(2-hydroxy-3-(3-methoxyphenyl)-2-methylpentanenitrile)

To 120 mg (0.41 mmol) C2 were added 1.5 mL of dry methanol and theresulting mixture was cooled to 0° C. 300 μl of an aqueous solution ofHCl (5 M) were added at this temperature and the mixture was stirred for3 h at RT. The organic solvents were evaporated under reduced pressureand a mixture of water and diethyl ether was added to the remainingresidue. NaHCO₃ was added until the aqueous layer had been alkalized.The layers were separated and the aqueous layer was extracted severaltimes with diethyl ether. The combined organic layers were dried overMgSO₄. The organic solvent was evaporated under reduced pressure and theremaining residue was dried in vacuo. 89 mg (99%) of C3 were obtained inform of a colorless oil.

Step c3: compounds C4(Z,E-3-(3-methoxyphenyl)-2-methylpent-2-enenitrile)

To 3.72 g (17 mmol) C3 were added 80 mL of toluene, 40 mL of pyridineand 81 mL of phosphoryl chloride (POCl₃), dissolved in 16 mL pyridine.The resulting mixture was refluxed for 1 h. After cooling, the reactionmixture was poured into ice water. Ethyl acetate was then added and thelayers were separated from each other. The aqueous layer was extractedtwice with ethyl acetate. The combined organic layers were washed withdistilled water, with a diluted aqueous solution of NaOH and were thendried over MgSO₄. The organic solvents were evaporated under reducedpressure and the remaining residue was dried in vacuo. CC (eluent:n-hexane/diethyl ether (10:1)) yielded 1.71 g (50%) of Z-regioisomer ofC4 well as 850 mg (25%) of the E-regioisomer of C4, each as a yellowishoil.

Step c4: compound C5 (Z,E-3-(3-hydroxyphenyl)-2-methylpent-2-enenitrile)

To 0.13 g D,L-methionine and 1.6 mL methane sulfonic acid were added 120mg (0.6 mmol) of C4. The reaction mixture was stirred for 16 h. Waterand ethyl acetate were added. After neutralization with solid NaHCO₃ thelayers were separated from each other. The aqueous layer was extractedtwice with ethyl acetate. The combined organic layers were dried overMgSO₄. The organic solvents were evaporated under reduced pressure andthe remaining residue was dried in vacuo. CC (eluent: ethylacetate/n-hexane (1:5)) yielded 90 g (80%) of C5 (mixture ofZ,E-regioisomers) in form of a yellow oil.

Step c5: compound 3 (3-(1-amino-2-methylpentan-3-yl)phenol)

70 mg (3.5 mmol) C5 were dissolved in 5 mL of dry methanol and placed ina hydrogenation apparatus. A small amount of a commercially availableRaney-Nickel (Ra—Ni) suspension (in water) covering the tip of a spatulawas added to the mixture. The resulting mixture was hydrogenated at roomtemperature under a H₂-pressure of 2 bar for 12 h (use of H₂: 128 ml).The solids were filtered off and the solvents of filtrate wereevaporated under reduced pressure and the remaining residue was dried invacuo. 70 mg (98%) of compound 3 were obtained in form of a brownishoil.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

The invention claimed is:
 1. A process for preparing a compoundaccording to formula (I)

wherein R¹, R² and R³ are each independently selected from the groupconsisting of H and C₁₋₄-aliphatic residues, or a physiologicallyacceptable acid addition salt thereof, said process comprising the stepsof: (b-I) converting a compound according to formula (B-I):

into a compound according to formula (I), by reductive amination of saidcompound according to formula (B-I) to a compound according to formula(I) performed in the presence of an amine of formula H—NR¹R² and/or asalt thereof and at least one reducing agent, wherein R¹, R² and R³ havethe above defined meanings, and (b-II) optionally converting thecompound according to formula (I) into a physiologically acceptable acidaddition salt thereof.
 2. The process according to claim 1, wherein saidcompound according to formula (I) is in the form of an isolatedstereoisomer.
 3. The process according to claim 2, wherein said compoundaccording to formula (I) is in the form of an isolated enantiomer ordiastereomer.
 4. The process according to claim 1, wherein said compoundaccording to formula (I) is in the form of a mixture of stereoisomers inany mixing ratio.
 5. The process according to claim 4, wherein saidcompound according to formula (I) is in the form of a racemic mixture ofstereoisomers.
 6. The process according to claim 1, wherein: R¹ and R²in formula (I) are each independently selected from the group consistingof H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyland, tert.-butyl; and R³ in formula (I) is selected from the groupconsisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec.-butyl, isobutyl and tert.-butyl.
 7. The process according to claim6, wherein: R¹ and R² in formula (I) are each independently selectedfrom the group consisting of H and methyl; and R³ in formula (I) isselected from the group consisting of H and methyl.
 8. The processaccording to claim 1, wherein said compound according to formula (I) isa compound according to formula (Ib)

wherein R¹ and R² are each independently selected from the groupconsisting of H and C₁₋₄-aliphatic residues or a physiologicallyacceptable acid addition salt thereof.
 9. The process according to claim8, wherein said process comprises: deprotecting a compound according toformula (B-I) in which R³ is other than H, to yield the compoundaccording to formula (Ib), and optionally converting the thus obtainedcompound according to formula (1b) into a physiologically acceptableacid addition salt thereof.
 10. The process according to claim 8,wherein said compound according to formula (Ib) is in the form of anisolated stereoisomer.
 11. The process according to claim 8, whereinsaid compound according to formula (Ib) is in the form of a mixture ofstereoisomers in any mixing ratio.
 12. The process according to claim 1,wherein said process further comprises a step (b-IV) in which a compoundaccording to formula (B-0-I):

wherein Hal is a halogen, is reacted with a compound of formula(B-0-II):

to produce the compound of formula (B-I).
 13. The process according toclaim 1, wherein said process further comprises a step (b-IV) which is a1,4-addition reaction of an α,β-unsaturated carbonyl compound and acompound according to formula (B-0-I):

wherein Hal is a halogen.
 14. The process according to claim 12, whereinHal of the compound of formula (B-0-I) is Cl, Br, or I.
 15. The processaccording to claim 14, further comprising forming a metal halide fromthe compound of formula (B-0-I) and a metal, in an inert reactionmedium.
 16. The process according to claim 15, further comprisingconverting the metal halide into an organocopper compound by reactionwith a copper precursor compound, and reacting the organocopper compoundwith the compound (B-0-II) to obtain the compound according to formula(B-I).
 17. The process according to claim 14, further comprising formingan organometal compound from reacting the compound of (B-0-I) with anorganometallic precursor compound in an inert reaction medium.
 18. Theprocess according to claim 17, further comprising converting theorganometal compound into an organocopper compound by reacting theorganometal compound with a copper precursor compound, and reacting theorganocopper compound with the compound (B-0-II) to obtain the compoundaccording to formula (B-I).
 19. The process according to claim 16,further comprising isolating and/or purifying the compound of formula(B-I).
 20. The process according to claim 18, further comprisingisolating and/or purifying the compound of formula (B-I).